Drugs for Bugs 2012-New IDSA Guidelines

Warren S Joseph, DPM, FIDSA discusses the new 2012 diabetic foot management guidelines published by the Infectious Disease Society of America. Dr Joseph discusses the impact and content of this document, citing examples of its application in relation to podiatric infections and the appropriate use of antibiotics.

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Warren Joseph
Warren S Joseph, DPM, FIDSA has disclosed that he receives Honorarium/Expenses, is a Consultant to and serves on the Speaker's Bureau for Pfizer and Merck.

Lecture Transcript

Jeff: Welcome back to the afternoon session. It is 1:00. We’re going to get started. We have an exciting lineup today starting with a good friend of mine, Dr. Warren Joseph. Most of you know Dr. Joseph. For those of you who don’t, you need to need to climb out of your holes. Dr. Joseph of course is probably the premier infectious disease podiatrist in the nation. Most recently, and I’m not going to go through his whole CV, but he always wants me to say that he was magna cum laude from the Scholl College of Podiatric Medicine, but he more importantly just contributed again to the literature, Moving the Science Forward with his participation, the development of the IDSA Diabetic Foot Guidelines. I can’t overemphasize the importance of this document to those of us who are treating diabetic feet, again moving the science. His first talk today will ironically be on the new IDSA Guidelines, Drugs for Bugs 2012, Dr. Warren Joseph.

[Applause]

Warren Joseph: It should have been summa. Thanks Jeff, I really appreciate it. As Jeff mentioned, very honored to be able to stand up here, and number one, thank you for inviting me, but to talk about the IDSA 2012 Guideline. Some of you who are familiar with our original document we published in 2004 in clinical infectious diseases. Well since that document had been published, it become the number one downloaded guideline from the IDSA website, which is www.idsociety.org. And between the 2004 publication and the new document in 2012, the original document was cited over 600 times in the index medical literature. It did have a major impact in the management of diabetic foot. We now have the new guideline. It was published in the June 15th issue of Clinical Infectious Diseases. It is available at the idsociety.org website. And it will be published in the executive summary at least, the whole document is 42 pages long with 350 references. But the executive summary of the document will be published in Journal of American Podiatric Medical Association in the January-February issue of 2013, so coming up shortly so you’ll see that. But I urge you to get it online. I will tell you, you will be held to this, especially the podiatrists here. It has been endorsed by the APMA. And as someone who does a significant amount of medical legal review work, I will tell you that I have had plaintiff’s attorneys wave the document in front of me when I’m on the stand as a defense expert. And say, “Well doctor, isn’t it true that these guidelines that you wrote said this, this and this?” And I’m like “Well I didn’t write that section of it, but okay.” We’re kind of stuck and you will be expected to know these guidelines. Now, a lot of things have changed with the guidelines, the entire way that the document has been put together. Now all IDSA guidelines have now been standardized to a question, answer and evidence summary recommendation sort of format, so it’s very easy to read. One of the things that has not changed is our severity classification. Now, all of you are involved in wound care, most of you are familiar with things like the Wagner classification or the Texas classification. The problem with the Wagner classification which CMS forces you to use in a wound center is that what grade Wagner do you have to have before the word infection appears? It’s going to be Wagner 3. Well, can’t you have a Wagner 1 that’s infected or Wagner 2 that’s infected? Sure you can. What we did we echoed what the International Working Group and the Diabetic Foot did is we came up with an infection severity scale. And you know what we used English. Basically we look at a foot and say it’s either noninfected, has a mild, a moderate or a severe infection. Now if that’s too difficult for you I have a new way to do it that’s even going to be better, if we ever rewrite these. About eight months ago I was lecturing in Charlotte, North Carolina. Trauma surgeon came up to me after the last year. She said “Can I run a case by you?” I said “Absolutely.” She said “I had a patient coming with a really, really bad infection.” I said, “Really, really bad, what’s that on the IDSA scale?” She said “severe”. She got me thinking. In another seven years if we do this again, actually IDSA wants to do it in five, we will go not infected, bad, really bad and really, really bad.

[Laughs]

I figure everybody will be able to remember that. I’m going to count on you knowing what this classification is, you should by now. It’s been around for a long time and we’re going to talk a lot especially about the noninfected side when I talked about bioburden and biofilms in one of my upcoming lectures. Now a lot of us Dr. Lipsky is the chairman of our committee and myself and others have tried to figure out the best way to present this in a lecture.

[05:08]

Well frankly, it’s impossible to do it because I’d put you to sleep, in half an hour I can’t give you 42 or 10 questions like 60 recommendations and all the evidence to back it up. I’m just going to pick a couple and let me show you a case. This is a patient of mine from last year who came in with what we classified as an IDSA severe infection. Now by definition, an IDSA severe infection is one in which the patient has the diagnostic criteria of Systemic Inflammatory Response Syndrome or sepsis. In this case it’s white count with 17,000, that’s above the 12,000 you need. His temperature was about 102, which is above the 101.3 you need. Right off the bat, he fits the criteria for systemic inflammatory response or sepsis. You can see here that he’s got these two draining sinuses on the medial side of the foot. His initial ulceration was under the plantar aspect. This is not bad but what happened is, he was told he needed more exercise by his family doc, so he figured with a hole on the bottom of his foot it was smart to go on a walk for a mile or so in the golf course. And he came in with this blown out infection into our emergency department. What do you do in a case like this? Well we’ve classified it. It’s IDSA severe. The first thing you need to do in a case like this, and again you can see the extent of cellulitis, is to take him for an I&D. And there’s no question nothing has changed in this regard. Incision and drainage of an abscess still takes primacy in the treatment of these acute infections, especially the patient is septic and where they have an abscess. Now if you look at this, what do you think about this? What do you think about this result. This is one day after the initial I&D. I don’t like it. The foot is still swollen, it still has that kind of acute fire engine red look to it. I wasn’t really thrilled with this. I called in our wound surgeon and I said, ”You know, I don’t like the way this looks.” And in particular, there was this one area, in circle here, right here. Do you see the color of the blanching, the color changes? That was very friable. I just touched that and it just started draining a little bit. They took him back to the OR the next day. Now, that’s gorgeous. I mean, to me this wound is absolutely beautiful. This is what we want to see. Now all the acute redness is gone. They still have that postinflammatory hyperpigmentation. You can see tendons. You can see where the dressing was. You can see wrinkles from the dressing. This is now a good looking wound. And three weeks later after he came back to the wound center, it look like this. This is just one of the wounds and one of our infections and the way we handled it. But let’s look specifically at how you would handle them in terms of bugs and drugs from an antibiotic standpoint. In this case, this patient grew out the two most common organisms we see in every diabetic foot infection Staph aureus, in this case it was methicillin-susceptible staph and group B streptococcus or Strep agalactiae. Now this patient was initially started on vancomycin and piperacillin/tazobactam. I actually don’t use that combination anymore. Currently I’m using vancomycin and Ertapenem. But given these bugs, now that we have these two organisms, what can you do in terms of antibiotics? What can you do in terms of antibiotics? Do we need a vanco pip/tazo? No, we don’t have MRSA, we don’t anaerobes, we don’t have gram-negatives. In the world of what’s called antimicrobial stewardship, that’s the big buzzword in the ID a pharmacy organizations nowadays, is we deescalated treatment. We went from broad spectrum initial therapy to a narrow spectrum coverage. And what antibiotic could you use to cover staph and strep? You use first generation cephalosporin. And in fact, we've put them on to cefazolin and he was discharged on cephalexin. You see a patient, you start broad, you deescalate when you can. Well what’s new in 2012? What do we have to talk about? Well, there’s a marked decrease in the amount of MRSA you see. I don’t know how many of you are noticing this in your centers. I’m getting some no headshakes here. Nationwide there actually has been a decrease in the amount of MRSA we’re seeing. And we’ve seen that at our hospital. We used to say and we still say, once MRSA always MRSA. I had a patient in three weeks ago who had been hospitalized multiple times for MRSA abscess of her abdomen and needed I&Ds. She came over with a foot infection. I started her on therapies if she had MRSA. Cultures didn’t grow MRSA. We’re starting to see less MRSA. That’s something that’s new. Here’s something else that’s new. We’re going to talk about this in the next lecture on multidrug resistant organisms, we’re seeing more multidrug resistant gram negatives. Our extended spectrum beta-lactamase producing gram negatives and our Kleb pneumo carbapenemase producing organisms.

[10:03]

Also new this was actually in 2011, the release of a fifth generation cephalosporin called ceftaroline, which is the first anti-MRSA cephalosporin. We’ll talk about that in the MRSA lecture, and the release of our revised IDSA guidelines. Let’s look at how the guidelines are written. Every committee was charged with coming up with a number of key questions to ask about your condition. Our committee identify 10 key questions about diabetic foot infections. In the case of our committee, each member of that committee was then given a question to have primary responsibility for. This was mine. Question number six was a question on, which antibiotic should I use and how should I modify regiments based on culture technique? See the questions and answers, the questions and recommendations are written in a very conversational term. It’s “How should I do this?” And the answer is, “Well we think you should do that.” It’s meant to be as if we’re just sitting and talking to each other. And again, standardized throughout all IDSA guidelines. What are some of our recommendations on the use of antibiotics? We recommend a clinically noninfected wounds not be treated with antibiotic therapy. We need to get away from this overuse of antibiotics because the wound is open and they have diabetes and they might get infected and we have to give it prophylactically. No, the only thing you’re doing is selecting alpha-resistant organisms. Now notice something else with this recommendation. The word strong low, what is that? Well, this is our grading of the evidence. In the past guidelines, and as many of you are aware, evidence has been graded by saying things like, this is Level 3b evidence, this is Level 2a evidence. Well besides Jeff Robins and Bob Frykberg, no one in this room knows what that means. They’re just [indecipherable] [12:06] enough to study this. But the point I’m trying to make is the average doc doesn’t get this. If I were to say your have 3b evidence, you’re not really sure. Well, all idea say guidelines, now use the British medical journal GRADE systems, G-R-A-D-E, that’s an acronym for something. But again, it uses English. And it’s very easy to understand, because what it does is it pairs the strength of the recommendation with an evaluation of the level of evidence. A strong low grade means we really believe this in the committee. But we can’t tell you why. We don’t have a lot of evidence to back that up. You know a strong high would be, we really believe this and we’ve got multiple, at least two randomized controlled clinical trials to back it up. And what’s very interesting and there have been a couple of studies that have looked at this that most evidence-based guidelines our recommendations is about strong low and I would say two-thirds of our recommendations in this guideline are strong low recommendations. That’s number one, we recommended clinically unaffected wounds not be treated. We recommend prescribing antibiotics for virtually all infected wounds but caution that it’s often insufficient unless combined with appropriate wound care. Antibiotics alone are not going to do it. It’s the old saying we’ve had in the diabetic foot world for years. It doesn’t matter what you put on in ulcer, what matters is what you take off the ulcer. You need to do the wound care, you need the debridement, you need the offloading. We recommend clinicians select an empirical antibiotic regiment, based on the severity of the infection and the likelihood of etiologic agents. Alright, well, what are the likely etiologic agents based on severity? For mild to moderate infections, in patients who have not recently received antibiotic treatment we suggest therapy just starting the anaerobic gram-positive cocci. As I mentioned before and I showed you in this previous case staph aureus and group B baby hemolytic strap are the primary organisms we’re seeing in the majority of diabetic foot infections. For most severe infections we recommend starting broad spectrum therapy, pending culture results and antibiotic susceptibility data. Now why is this? If someone comes in and they’re sick like our patient here, I can’t just give them cefazolin hoping that it’s just staph and strep. It turned out to be but I can’t do that, because I can’t afford to be wrong. What we recommend is for these more severe infections you start broad. You can’t miss it, you have to start broad. And then if the patient comes back you can deescalate down to the organisms you find based on culture results and antibiotic susceptibility as we say here.

[15:04]

This has led some of us in the diabetic foot world to talk about the concept of the two-headed snake. And this a slide courtesy of Tony Burns [phonetic] the co-chair committee out of the UK, he’s like a master of PowerPoint slides. But this demonstrates the two-headed snake or the head of the snake philosophy. Imagine a snake, and that snake has a head or two heads, it consists of staph and group B beta-haemolytic strep. And the body of the snake are all of those other organisms, all the gram-negatives, the Enterobacteriaceae, the anaerobes and some of those other gram-positives like the coagulase negative staphs. What happens if you just hit the staph and strep. What happens if you just use an anti-staph and strep antibiotic? When you cut off the head of the snake, the body dies. Now we know this is probably true in our more mild infections, even though we don’t have good data to back it up, so it’s kind of a strong-weak recommendation. With polymicrobial flora, it may worsen the prognosis. But in severe infections and osteomyelitis, we’re not sure we can go this way. But at least for our mild, and this is what we say in the guideline, at least for our mind and many moderate infections, we can direct therapy against the aerobic gram-positive cocci staph and strep. Now what antibiotics would you use for staph and strep, after all we’re talking bugs and drugs? Fortunately there’s a lot we can use for staph and strep. For an IDSA mild infection, I’m happy using an antistaphylococcal or oral cephalosporin. It’s easier to say ASOC. What do I mean by that? Cephalexin. If you want to use cephalexin use cephalexin, it’s fine, or any of the derivatives of cephalexin. Amoxicillin clavulanic acid, great antibiotic. I stopped using it a little bit. It works really, really well. But here’s my problem with that drug. How many people in this room have personally taken Augmentin? Yeah, alright. Number one, how big is the 875? Yes, it’s like a horse pill. Is it a suppository or is it a pill? You don’t really know. And I had about a year ago, I had an emergency root canal and the periodontist gave me a prescription for 875 Augmentin and I know I have to take it with food and a full glass of water. Well let me tall you something, I call it patient’s revenge, not Montezuma’s revenge. For all the patients I’ve given this to, and I didn’t get diarrhea I know too much information. But within 20 minutes of taking every dose, I felt that my stomach was going jump out of my abdominal wall. It was an unbelievably uncomfortable drug to take so I don’t take it a lot. I don’t give it a lot anymore. Clindamycin, still a good drug to go, very good drug to use in fact, everyone it’s clindamycin, 300 milligrams q. 12 or q. 8 hours. “Oh they’re going to get C. diff” every antibiotic can give C. diff. Clindamycin has an advantage because it’s a bacterial protein synthesis inhibitor. What’s that mean in English? All these staphs and streps produce toxins. These toxins, these virulent factors are proteins. By giving the patient an antibiotic that’s a protein synthesis inhibitor, you can decrease virulence of the infection. You see clindamycin used for instance a lot in cases of necrotizing fasciitis. It’s not used necessarily for its antimicrobial activity. It’s used because of its antitoxin activity. One other drug shares that property and that happens to be linezolid also is a protein synthesis inhibitor. Oral penicillin, age-resistant penicillin, so I personally don’t use them. They’re inconvenient to use, cloxacillin, dicloxacillin, drugs like that. They’re four time a day. No patient takes a drug four times a day. It just doesn’t happen. For our moderate to severe infections, what do we use? Well, beta lactamase, beta-lactam inhibitor compounds, ampicillin-sulbactam, Unasyn, piperacillin/tazobactam, Zosyn, fine. Again, I use ertapenem, cefazolin and clindamycin or vancomycin in patients who are truly penicillin and cephalosporin allergic. You could use any of those drugs. And in our guidelines, we came up with a table. It’s a little complicated to see it on the slide. It looks much better laid out on the guideline. We recommend antibiotics for mild infections and we recommend antibiotics for moderate to severe infections. And we give comments about each of those antibiotics. Currently in the United States, only three antibiotics actually carry the indication for complicated skin and skin structure infections, including diabetic foot infections without concomitant osteomyelitis. And they are the ertapenem 1 gram q. 24 I.V., piperacillin/tazobactam 3.375 q. 6 or 4.5 q. 8, and for MRSA, the linezolid 600 milligrams p.o. or I.V. q. 12 hours. These are the only three antibiotics with a diabetic foot indication and I will tell you as we sit here in late 2012, they will be the only three antibiotics, because the FDA in their current guidance called the Acute Bacterial Skin and Skin Structure Guidance, they’ve actually eliminated diabetic foot.

[20:14]

There is no pathway for any pharmaceutical company to get an antibiotic approved for diabetic foot infections as we sit here today. And I have been in front of the FDA twice in the last eight months. And I still have the dent in my head from banging my head against the wall. They’re very nice people, but their statisticians are telling them there is no proof, there is no historical evidence that antibiotics play a role in the treatment of diabetic foot infections. Yeah, I’ve only got 10 minutes left in this lecture I could spend at least that much talking about their whole philosophy on that. Catch me outside if you want to talk about it. Well what about MRSA? We’re going to talk a whole lecture about MRSA but in diabetic foot when do we need to use MRSA? What do we say in the guidelines? We say we recommend a definitive therapy be based on both the results of an appropriately obtained culture and sensitivity testing, and the patient’s clinical response to the empirical regimen. What’s that mean in English? You give a patient an antibiotic, it doesn’t work against MRSA. And they do really, really well. And four days later the culture comes back and it shows MRSA. It doesn’t mean you have to put them on MRSA therapy. Because we come down and say, it’s based on the patient’s clinical response. But we do consider adding empirical MRSA therapy in three distinct situations. Number one, as I said before, once MRSA always MRSA. If the patient has a prior history, we assume they may still have it. We start them empirically with it. If your local prevalence of MRSA is high, we don’t define what that means. But frankly at our hospital, we’re at about 65% MRSA rate on our antibiograms. If you’re in some out of the woods sort of play somewhere and you’re at 40% MRSA, maybe you don’t need definitive MRSA therapy or the empirical MRSA therapy. And then finally, we say that, again, if the infection is clinically severe, as I mentioned before, we can’t afford to be wrong, we’re going to start MRSA therapy until proven otherwise. And we’re going to talk in the next lecture about some of the treatments for MRSA both mild and moderate to severe. Well, let’s get to this whole concept of deescalation therapy. Again, if you have a mild infection, we know it’s staph and strep, you want to cover your gram-positives. Are the patients at risk for MRSA. Have they had previous MRSA, do you have high prevalence of MRSA. If no, just use a cephalosporin. Use amoxicillin clavulanic acid. But if they’re at high risk for MRSA, they’ve had MRSA before, you’ve got a lot of MRSA in your community, then I would use doxycycline or minocycline. Doxycycline 100 milligrams q. 12 hours. Notice I don’t say trimethoprim-sulfa. I’m not a believer in using trimethoprim-sulfa, Bactrim. There’s a reason we stopped using that drug 40 years ago. It has to do with all the adverse events associated with it. I’d rather see doxy used. If the patient can get it, linezolid even though not for mild infections. Clindamycin you cannot count on because of the inducible macrolide-lincosamide-streptogramin gene. That’s for mild infections. Well for moderate to severe infections, again, we talked about starting with MRSA therapy. And what would you use? Well, maybe we use vanco, we could linezolid. I don’t use tigecycline. There's Lee Rogers put this slide together, I disagree with that. I don’t use that for a number of reasons. In fact, there are some studies that are now looking at all cause mortality rates on tigecycline being higher than with other antibiotics, with comparable antibiotics. You start something like ertapenem, vancomycin, pip/tazo vancomycin or linezolid. And then when you get the culture result back, you deescalate if you don’t need it. But what about strep, both for drug, what antibiotic do you use for strep? What’s great about group B strep? There’s no resistance. Just about everything will work. Any beta-lactam is going to work, so any penicillin, even old fashion penicillin, amoxicillin, which is really no reason to use, amoxicillin clavulanic acid, cephalexin, clindamycin. Even, heaven forbid, I don’t want you to use, quinolones have some group B strep activity. Group B strep, pretty much anything you use for staph will also hit group B strep. I just want to finish up with talking about pseudomonas. I like to talk in our profession about how we have a pseudomonaphobia. Now I mentioned on the cover slide, I have my blog addressed LE infections for lower extremity leinfections.com. I’m guilty. I haven’t put a new post up in about three months. I’ve just been too busy running around. I promised, I’m home for a couple of weeks now I’ll put some posts up. But I did a post about a year or so ago, which I called Pseudomonaphobia because everyone, at least in podiatric medicine and surgery, has this Pseudomonaphobia.

[25:07]

You didn’t go a residency interview where you weren’t asked how to treat pseudomonas. Yet there’s only one clinical situation in which pseudomonas is reliably thought to be a pathogen in the foot. What is that? You know, puncture wound osteomyelitis. I don’t buy that through the shoe or through the sneaker thing, just puncture wound osteomyelitis. Ninety plus percent of the time, pseudomonas. But in diabetic foot, that’s not true. Let’s look at the evidence to back that up. This study showed clinical response rates in patients who grew pseudomonas from a complicated skin and skin structure infection including diabetic foot. The gram study in clinical infectious diseases back in 2002 was the pivotal trial in which ertapenem received its indication for complicated skin infections. In patients who grew pseudomonas, they got better 70% of the time on ertapenem, 60% of the time on pip/tazo. Well, let me tell you this, ertapenem doesn’t work against pseudomonas, pip/tazo does. Yet the patients actually did better on an antibiotic that didn’t work against the organism. And this was almost exactly duplicated. In 2005 with the SIDESTEP study, Ben Lipsky’s pivotal work on ertapenem for diabetic foot infections, 76.9% of patients on ertapenem got better, who grew pseudomonas 70% on pip/tazo. It doesn’t mean their ertapenem is a better antipseudomonal drug, it just means the pseudomonas doesn’t matter. Let’s forget about ertapenem. Full disclosure I’m a consultant and a speaker from Merck, I’m consultant and a speaker for Pfizer, but let’s talk about a drug and I’m not a consultant or speaker for this drug. Ceftaroline, this is that fifth generation cephalosporin we’ll talk about in the MRSA lecture. And there are two identical clinical pivotal trials called the CANVAS 1 and 2 studies. They had over 1,300 patients, in those patients who grew pseudomonas, 80% of them got better on ceftaroline. Ceftaroline doesn’t work against pseudomonas. That led to this quote, “The demonstration of efficacy in patients with Pseudomonas aeruginosa, receiving ceftaroline, a pathogen against which ceftaroline has little activity most probably reflects the presumptive role of Pseudomonas aeruginosa as a colonizer rather than a true pathogen in many of these infections.” We need to get away from thinking that we need to cover pseudomonas. If you do get pseudomonas from a deep surgical wound, then yes there are ways to cover it. I don’t like quinolones. I think the only place to use quinolones is to treat pseudomonas, if it’s still sensitive. Unfortunately because of the overuse of the quinolones many pseudomonades are not currently susceptible to the quinolones anymore. Other than that, everything we have is intravenous, ceftazidime a third generation cephalosporin, cefepime, some people consider it a fourth generation cephalosporin. Aztreonam, with or without an aminoglycoside, ladies and gentlemen there’s no reason in modern medicine to ever treat a complicated skin and skin structure or diabetic foot with an aminoglycoside. And let’s not even get into that whole thing about Gustilo’s Classification with grade 3 open fractures using aminoglycoside. That was so incredibly flawed and back in the 1970s before any new antibiotic was out there that covered pseudomonas, don’t get me started on that. If you want to, meet me in the exhibit hall, we’ll talk about it. Again, you don’t need to use aminoglycosides. In fact, from a medical-legal perspective, I find it really tough to defend aminoglycoside cases and I’ve seen a couple across my desk with autotoxicity from aminoglycosides, where patients literally bounce off walls for the rest of their lives. And I don’t care if you got an ID involved or not, if it’s your patient, you’re getting sued. To me this is what we usually grow pseudomonas out of. You can see this clean heel decub. There’s good granulation around the periphery, but sure, there’s some slough and that slough happens to have some green discoloration. If you take a swab culture of this, you’re going to grow pseudomonas. But is there any sign of clinical infection around here? No, something like this I would just treat it topically. I would just treat it locally. I got it right here, 1 minute 43 and I in fact conclusion. He’s being a good moderator. Are you going to turn the microphone off? I’ll tell you this lecture I could do in 30 minutes, the next two I’ve got that’s going to be real tough to put those into 20 minutes, it’s going to be called the fast talking one. Head of the snake, remember most of these infections in the diabetic foot are caused by staph and strep. Consider deescalation therapy.

[30:01]

If you start somebody broad, once you get the culture results back, good antimicrobial stewardship principles call for you to narrow the spectrum. The whole idea of antimicrobial stewardship is using the narrow spectrum antibiotic for the shortest period of time. I’ve actually got a manuscript paper coming out in the January-February issue of JAMA on antimicrobial stewardship for podiatrists. I did it with Bob Smith who’s a podiatrist and a pharmacist. Watch your vancomycin MICs, we’re going to talk about that later, and be alert for the concept of pseudomonaphobia. With 42 seconds left, thank you.